Round-up March 3rd – March 17th

A mother whose son died in 2008 is suing Quest Diagnostics for reporting a variant as a VUS, when there was sufficient evidence for it to be pathogenic — the claim is that if it had been reported as pathogenic, his treatment could have been changed, and his life potentially saved. The case highlights the importance of variant classification decision transparency. One lawyer’s commentary: there is precedent for a court saying that in hindsight “although everyone was doing things a certain way, they shouldn’t have been. It could turn up the pressure [on labs’] handling of VUS. It could force labs to be more collaborative and share data out of fear.” Heartbreakingly, and raising a whole set of other issues, the mother initially refused follow-up genetic testing (context is that a mitochondrial variant was suspected): “I didn’t want someone to confirm that it was me that killed my child.” The GenomeWeb write-up is a must read: https://www.genomeweb.com/molecular-diagnostics/mothers-negligence-suit-against-quests-athena-could-broadly-impact-genetic

A study that compared WES as a first-tier test to standard of care came out favorably for WES: “Of 80 enrolled infants, 46 received a molecular genetic diagnosis through singleton WES (57.5%) compared with 11 (13.75%) who underwent standard investigations in the same patient group.” http://www.nature.com/gim/journal/vaop/ncurrent/full/gim20161a.html

But a meta-analysis, which focuses on common diseases, has found “Expectations that communicating DNA-based risk estimates changes behavior are not supported by existing evidence.” http://www.bmj.com/content/352/bmj.i1102.

An opinion piece in JAMA, http://jama.jamanetwork.com/article.aspx?articleid=2498853, argues that the variant classification system is not up to muster: “The information the physician usually needs is the likelihood of disease among patients with the variant (penetrance), and an assessment of whether the genetic profile requires action or not.” The authors seek a quantitative disease-risk estimate, as GWAS attempted to do, and call for the sharing of full genotype-phenotype data.

I think the way the variant classification advocates would respond is to say that classification is only one part of interpretation. A variant’s classification is the same no matter its context, and independent of penetrance. A variant’s classification should be teamed with the penetrance of the variant and whether the inheritance mode is consistent to give an interpretation.

An antigen is any substance that causes the immune system to produce antibodies against it. Some proteins, when mutated (as detected by sequencing), can become neoantigens. If there are Tcells that react to these neoantigens, these neoantigens can become targets for therapy, by a vaccination approach. This would be done in combination with Immune checkpoint inhibitors, drugs that take the ‘brakes’ off the immune system. This work appears in Science, http://science.sciencemag.org/content/early/2016/03/02/science.aaf1490. Connecting success of the idea with the underlying genetics, the authors note that: “Tumors with both a high clonal neoantigen burden and low neoantigen ITH (intra-tumor heterogeneity) were associated with significantly longer progression free survival.”

And while on the subject of bacteria, a group of researchers have published an editorial in the Journal of Alzheimers drawing attention to the possible role of microbes in causing Alzheimers, a link they claim has been “neglected” for too long, and needs urgent further research: http://content.iospress.com/articles/journal-of-alzheimers-disease/jad160152. The authors point to the fact that APOEɛ4 – which makes one in five people more susceptible to Alzheimer’s disease, also raises their susceptibility to infectious disease.